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Patient Presentation A 15-year-old female came to clinic at the end of the summer for her health supervision visit and sports physical. She played volleyball and had been spending significant amounts of time outside playing sports over the summer. She had no concerns except that she had noted darker brown patches on sunexposed areas of her arms, thighs, face and upper chest. She had noticed them more over the course of the summer. They caused no pain or pruritis and she denied any swelling, erythema or scaling. She denied any drug use including not wearing sunscreen, as she stated, “Why should I wear it? I just tan and it gets in my eyes and sticks to the sand or grass when I play sports.” The past medical history and family history were non-contributory.

The pertinent physical exam showed a healthy female who was 90% for height and 25% for weight and was tracking appropriately. Her skin examination showed skin that was overall tanned, with what looked to be normal variations in skin tone, including her face. She had 1 cafe-au-lait lesion on her left shoulder/upper back that was 1.5 cm in size. She had no freckling of her face or axilla. She also had some mild closed comedomal acne on the bridge of her nose.

The diagnosis of a healthy female was made with tanning and one cafe-au-lait lesion, and mild acne. The pediatrician recommended for her to always use sunscreen especially as she lead an active lifestyle and was outdoors often. “Even if you tan, you still need to use sunscreen to prevent the risk of premature aging of your skin and skin cancer. Especially if you are outdoors a lot you need to have your skin checked at least every year and maybe more often as you get older. You can also use some benzoyl peroxide for your acne.” the pediatrician counseled. The teenager looked unimpressed with the diagnosis and counseling. “If you would like, I can refer you to the dermatologist who may have more specific recommendations for sunscreen and monitoring, and your acne,” she also offered. The teenager started to smile when the referral was offered.

DiscussionSkin color is primarily due to genetic factors. Melanocytes are usually found in skin in the basal layer of the epidermis which is also where the melanin usually lies. There are a range of normal skin phenotypes that have been described by Fitzpatrick and range from I-VI:

Melanocytes in increased numbers, producing more melanin or in abnormal locations can cause hyperpigmentation. Here are some examples:

Epidermal melanosis – increased melanin but normal number of melanocytes

Cafe-au-lait spots

Urticaria pigmentosa

Dermal melanosis – melanin in the dermis

Drug eruption

Incontinentia pigmenti

Lichen planus

Post inflammatory hyperpigmentation

Mixed – melanin in epidermis and dermis

Post inflammatory hyperpigmentation

Just like hypopigmentation (which can be reviewed here), hyperpigmentation can be worrisome for many families because of cosmesis and the worry that “something is wrong.” The normal natural changes in skin-tone over the year due to different light exposure and wide variations within individuals is not something that many people are aware of. Post-inflammatory hyperpigmentation is one of the most common causes of hyperpigmentation. Treatment can be difficult but mainstays are bleaching agents and laser therapy.

Palmar or plantar hyperpigmentation – can also be due to medications or Addison’s disease

Abnormal

Post-inflammatory hyperpigmentation

Addison’s disease

Drugs

Dyschromatosis symmetric hereditaria

Familial progressive hyperpigmentation

Fanconi’s anemia

Lentiginosis – Peutz-Jeghers, LEOPARD syndrome

Lentigo solaris

Linear or whorled nevoid hypermalanosis

McCune-Albright syndrome

Melasma – due to pregnancy, contraceptives but also cosmetics, phototoxic drugs, anti-convulsants and UV-radiation

Metabolite accumulation – Gaucher’s disease, hemochromatosis

Neurofibromatosis type 1

Nevus of Ota or Nevus of Ito – grey-brown to blue color, often presenting around the time of birth. Nevus of Ota is on the face (Trigeminal nerve distribution – ophthalmic and maxillary branches), Nevus of Ito on shoulder and neck.

Renal failure

Vitamin B12 deficiency

Xeroderma pigmentosum

Questions for Further Discussion
1. How much SPF sunscreen factor is recommended? A review can be found here
2. What are the risks of ultraviolet light?

Patient Presentation A 38 1/7 week gestation, newborn girl was delivered by normal spontaneous vaginal delivery, with Apgar scores of 8 at 1 minute and 9 at 5 minutes, to a 27 year old Hispanic mother with 1 previous living child. The past medical history was significant for the mother having close monitoring during the 3rd trimester because of symmetric small-for-gestational age (SGA) in the fetus. The mother’s other child was also SGA with a similar pattern and currently was a small but healthy 33 month old. The family history was positive for the mother’s sister who had an infant die in utero in the first trimester. There was diabetes and obesity in family. The family had a relatively shorter stature. The mother was average size for her family and was 5’1″, and the father was tall for his family and was 5’7″ with mid-parental height at 10-25%.

The pertinent physical exam at birth showed a small, thin infant with a wrinkled face and a lusty cry. Her weight was 2674 grams (5-10%), her length was 47.5 cm (10-25%) and her head circumference was 33 cm (10-25%) using World Health Organization growth charts. There were no obvious congenital abnormalities and she had a 3-vessel umbilical cord. She had thinner skin and smaller amounts of subcutaneous fat and musculature. Her Ballard examination was scored 34 (a score of 35 corresponding to a 38 week infant). The diagnosis of an infant with symmetric SGA was made. It was felt this was due to a constitutionally small infant.

The patient’s clinical course over the next several hours found that she had normal glucose tests when monitored on the neonatal glucose protocol. By discharge on day 2 of life the infant was feeding every 1-3 hours for about 30 minutes. She was having 2-3 wet diapers/day and had lost 113 grams or about a 4% decrease from her birth weight. At followup on day of life 5, she had continued to nurse well along with some formula supplements that had been given when the mother was sleeping. She had lost another 46 grams and had decreased 6% from her birth weight. Her mother felt that her milk had come in the day before. On followup at day 7 of life the infant had gained 33 grams since the previous visit, and at day 15 she was past her birth weight. She continued to be a smaller infant growing around the 10% for the first several months of life. At age 15 months she was around the 10-25% for weight, and 25% for height and head circumference and was growing appropriately.

DiscussionIntrauterine growth retardation or fetal growth retardation is due to a pathological process that causes decelerated fetal growth velocity. Small-for-gestational age (SGA) is an infant with growth parameters below the normal range for gestational age. More commonly, SGA is defined as a birth weight < 10% for gestational age. This may be due a pathological or non-pathological process (e.g. constitutionally small fetus). Using these standards, remember that 10% of all infants will be < 10% for weight, and they do not necessarily have an underlying problem and infants who are constitutionally small do not have increased perinatal mortality and morbidity. SGA and IUGR are not synonymous. IUGR always refers to a pathological process, whereas SGA may or may not be a pathological process but just a small infant.

SGA infants classically appear small with thin, loose skin, little subcutaneous fat and decreased muscle mass. The umbilical cord is thin. The face has a shrunken or “wizened” appearance often. Therefore, the gestational age at birth is best determined by the neurological assessment than by the physical appearance.

Symmetric SGA usually reflects a fetal problem and usually occurs in the first trimester with overall growth restriction. The long-term prognosis is not as good as asymmetric SGA reflecting an increased risk underlying disease processes such as a genetic abnormality.

Constitutionally small infants usually have symmetric SGA.

Asymmetric SGA usually reflects a placental problem and usually occurs in the 2nd and 3rd trimesters with growth restriction that is discordant. Usually head circumference is preserved, with length somewhat affected, and weight affected the most.

The earliest gestational ultrasound scans are most accurate for recognition of SGA and especially for correct dating of the pregnancy. Special ultrasound growth curves are used which use initial maternal height and weight, ethnic origin, fetal gender and parity. Abdominal circumference is the most accurate ultrasound measurement to determine SGA.

“The recurrence risk for SGA is 29% if a previous pregnancy was affected and 44% if two previous pregnancies were affected.”

Questions for Further Discussion
1. What are common treatments given to, or monitored for, in SGA newborns?
2. What could be included in an evaluation for SGA?
3. What are common causes of large for gestational age (LGA) infants?

Patient Presentation A pediatrician received a late afternoon phone call from the state’s newborn screening program, about a 4-day-old female whose neonatal screening test was presumptively positive for severe-combined immunodefiency (SCID). The parents had already been contacted and were already planning on coming to their first office visit after discharge the next day. The program coordinator had faxed full information about what the pediatrician should do during the visit and also information for the parents. “The most important part is to make sure that the repeat testing is transported right away to our hospital, so we can get the testing done correctly,” the coordinator stated. “The second most important part is to make sure that the infant isn’t around anyone who is sick because they can get sick very quickly,” she also said.

The following day, the staff brought the infant to a room immediately and weighed and measured her. The medical history showed that she was a full-term infant born to a G2P2 mother without problems during pregnancy or delivery. The baby had no problems during hospitalization. Her mother reported that she was breast-feeding about every 2-3 hours with many wet diapers. Her stools had transitioned and her mother was not concerned about jaundice. The family history was negative for any genetic diseases or children who died young or unexpectedly.

The pertinent physical exam showed an alert female with a weight of 3180 g down 6% from birth but only 2% from discharge. Her length and head circumference were 50-75%. She had no rashes, but she had a black-blue nevus over her sacrum. No abnormal physical findings were noted.

The diagnosis of a healthy appearing infant with a positive neonatal screening test was made. The repeat neonatal screening test was sent after the visit and routine care was discussed as well as infectious disease precautions were re-iterated. The next day the program coordinator called to tell the pediatrician that the repeat testing was totally normal. The original testing was a false-positive result. She asked that the pediatrician contact the family with the results and said that no special precautions needed to be followed. She wanted the family to also know that if they had other questions they could always call the program, but that she was happy that the family had a healthy infant.

DiscussionSevere-combined immunodefiency (SCID) is actually a group of inherited disorders with an absence or dysfunction of T, B and NK cells that results in severe dysfunction of the immune system. SCID is a primary immunodeficiency. SCID was thought to be a rare disorder but with the advent of neonatal screening the incidence in the US general population is estimated at ~1 in 58,000 live births, but with numbers higher or lower depending on the specific population.

Patients often have failure to thrive, oral candidiasis, and diarrhea as infants as well as a variety of infectious diseases. They can also have interstitial lung disease due to Pneumocystis jiroveci or graft-vs-host disease because of maternal lymphocyte engraphment. Without treatment to reconstitute the immune system, patients usually die at < 2 years of age.

Initially SCID was classified by if the patient was T or B cell deficient or normal, with subsets of NK deficiency or not (i.e. T–B– NK –,T–B+ NK +, etc.) Molecular genetics now has identified multiple genes that are associated with different SCID phenotypes. The genes can cause disease by affecting the hematopoietic precursor survival, cause problems with cytokine signaling, allow toxic metabolite accumulation, genetic recombination, and other mechanisms. Most SCID genes have an autosomal recessive inheritance. Thymic abnormalities are often grouped with SCID because of phenotypic and genetic similarities. DiGeorge syndrome (22q11 deletion sequence) includes congenital athymia which causes similar immunological problems because the T-cells do not have a thymus to properly develop within. DiGeorge syndrome also has other problems associated with it and a review can be found here.

Curative treatment is available through allogeneic hematopoietic stem cell transplantation and is considered the preferred treatment. Gene therapy is also potentially curative for 2 different types of SCID (ADA and IL2RG genes). Adenosine deaminase infusions are also an option for ADA deficient SCID but are not curative. Studies have shown > 90% long-term survival after transplantation when infants are < 3.5 months of age, and have a sibling match.

A review of primary immunodeficiencies can be found here. A review of potential testing to do for a suspected immunodeficiency can be found here.

Learning Point
In the US, the Department of Health and Human Services has an advisory panel that recommends a core panel of congenital disorders that are recommended to be screened for. SCID was added to the core panel in 2010. Screening for SCID is done through TREC testing (T cell receptor excision circles) using the Guthrie blood spot cards. T cell specific confirmatory testing using flow cytometry and other testing needs to be carried out if TREC is positive.

TREC testing does not identify all forms of combined immunodeficiency or atypical SCID. Other types of testing such as KREC (kappa-deleting recombination excision circles) may increase the ability to identify other forms for SCID. Prenatal testing in high risk families is available.

Questions for Further Discussion
1. Who was “David the Bubble Boy” and what is his link to SCID?
2. What are indications for stem cell transplant?
3. What are the differences between stem cell transplant and gene therapy?
4. What disorders does your state or country test for on newborn screening?

Patient Presentation A 17-month-old male came to the emergency room with emesis and diarrhea for 1 day. His older sister had had similar problems 3 days before but after 36 hours improved. He had emesis three times of stomach contents. He had diarrhea multiple times of brown watery stool that leaked out his diaper twice. There was no blood or mucous in either fluid. He was afebrile. He was drinking small amounts of oral rehydration solution but had not had a wet diaper for 6-8 hours. His past medical history was significant for Silver-Russell syndrome that was diagnosed after birth because of being small for gestational age. He had postnatal growth retardation and was followed closely by gastroenterology. He had required a nasogastric feeding tube for a few months but he had stopped it 9 months ago and currently was growing at the 1st percentile. He saw multiple other services for his overall care, and had been hospitalized for dehydration or feeding difficulties twice in the past. The family history was negative for any genetic or neurological diseases. The review of systems was otherwise normal.

The pertinent physical exam showed a very tired-appearing, small, thin male sitting in his mother’s lap. His weight was down 680 grams from a clinic visit earlier in the week. He had triangular face with a prominent forehead and slightly low-set ears. His mucous membranes were slightly tacky and his capillary refill was 3+ seconds. HEENT examination was otherwise normal as were his heart and lungs. His abdomen showed increased bowel sounds without pain or guarding. Extremities showed a short male with thin musculature.

The diagnosis of a patient with gastroenteritis in the setting of Silver-Russell syndrome was made. Fluid resuscitation was given in the emergency room, but the patient refused to drink and continued to have emesis and diarrhea and so he was admitted. The patient’s clinical course revealed that the emesis and diarrhea resolved by day 2, but the patient was refusing to drink enough. Nutritional services, speech therapy and gastroenterology continued to work with the family and by Day 5 of admission he was taking his usual feedings and was discharged.

DiscussionSilver-Russell syndrome (SRS) is a rare genetic syndrome first characterized by Silver in 1953 and Russell in 1954. Patients with SRS have characteristic growth patterns and clinical findings, although within an individual patient there are phenotypical differences. Patients are born small-for-gestational age (SGA) but have a relative macrocephaly. There is postnatal growth failure and difficulty feeding, with a very low body mass index. Body asymmetry (e.g. hemihypertrophy) and facial features (i.e. protruding forehead, triangular facies, micrognathia, dental anomalies, downturned mouth corners, and ear anomalies) are characteristic features.

Patients need multidisciplinary specialist care. SGA and feeding difficulties make patients often difficult to manage. Patients have lower muscle mass and excess calories quickly go to excess fat mass if patients are overfed. Gastroenterology, nutrition, speech therapy and psychology often manage these problems. Short stature can be marked (< 3 standard deviations below adult height) and recombinant growth hormone is used for treatment. Body asymmetry may need surgical treatment. Facial malformations can lead to dental, speech and otolaryngological problems that need to be addressed. Data on cognitive development is small, but if developmental or intellectual disabilities are identified they also need multimodal treatment.

Learning PointGenomic imprinting is an epigenetic modification process, which allows a gene to be expressed in a single allelic, parent-of-origin specific manner. The imprinting occurs in gene clusters that are differentially methylated in both DNA and histones. These epigenetic methylated marks “…are acquired during gametogenesis, and normal embryo development is dependent on their maintenance after fertilization and during embryogensis.” This methylation process does not alter the gene sequence and is inherited independent of classic Mendelian inheritance. Imprinted genes control growth, development and metabolism. More than 100 imprinted genes have been identified in mice. About half of these are conserved in humans.

SRS generally is considered a sporadic inheritance, but there are some families where recessive, dominant or X-linked have occurred. Recurrence risk is considered low, but appropriate genetic counseling is important. Imprinting on chromosomes 7, 11, 15 and 17 have been recognized.

Currently known human imprinting disorders include:

Angelman syndrome

Beckwith-Wiedemann syndrome

Kagami-Ogata syndrome

Maternal uniparental disomy of chromosome 20 syndrome

Precocious puberty syndrome

Prader-Willi syndrome

Pseudohypoparthyroidism Type Ib

Silver-Russell syndrome

Transient neonatal Diabetes Mellitis 1

Temple syndrome

Imprinting in one area of chromosome 11 appears to cause some cases of SRS if transmitted maternally, but causes some cases of Beckwith-Wiedemann syndrome if transmitted paternally.

Questions for Further Discussion
1. What are indications for genetic counseling?
2. What support organizations for rare disorders are available locally or nationally?

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